1. Field of the Invention
The herpes viruses include the Herpes Simplex virus (HSV), comprising two closely related variants designated types 1 (HSV-1) and 2 (HSV-2). These types cross react strongly but can be distinguished by neutralization titrations. HSV-1 and HSV-2 are responsible for a variety of human diseases, such as skin infections, genital herpes, viral encephalitis and the like.
HSV is a double-stranded DNA virus having a genome of about 150 to 160 kbp packaged within an icosahedral nucleocapsid enveloped in a membrane. The membrane includes a number of virus-specific glycoproteins, the most abundant of which are gB, gC, gD and gE, where gB and gD are cross-reactive between types 1 and 2.
It is a matter of great medical and scientific interest to provide safe and effective human vaccines against both HSV-1 and HSV-2 and, where infection has occurred, therapies for treatment of the disease.
One promising approach to the production of human vaccines against HSV has been the use of isolated glycoproteins, which have been shown to provide protection when injected into mice subsequently challenged with live virus. However, the availability of the Herpes Simplex glycoproteins has heretofore been primarily dependent upon the growth of the virus and the isolation of the membranous proteins. The problems of commercial production of the glycoproteins associated with the handling of a dangerous pathogen, the maintenance of the virus in cell culture, the isolation of the glycoproteins free of the viral genome or portions thereof, have substantially precluded the use of the glycoproteins as vaccines. It would therefore be desirable to provide human vaccines employing glycoproteins produced by methods other than by growth of the virus and isolation of the membranes proteins.
2. Description of the Relevant Literature
Eberle and Mou, J. of Infectious Diseases (1983) 148:436-444, report the relative titers of antibodies to individual polypeptide antigens of HSV-1 in human sera. Marsden et al., J. of Virology (1978) 28:624-642, report the location of a gene for a 117 kilodalton (kd) glycoprotein to lie within 0.35-0.40 map units on the genetic map of HSV by intertypic recombination between HSV-1 and HSV-2. Ruyechan et al., ibid. (1979) 29:677-697, also report the mapping of glycoprotein B gene to lie between 0.30-0.42 map units. Skare and Summers, Virology (1977) 76:581-595, report endonuclease cleavage sites for EcoRI, XbaI and HindIII on HSV-1 DNA. Roizman, Ann. Rev. Genetics (1979) 13:25-57, reports the organization of the HSV genomes. DeLucca et al., Virology (1982) 122:411, map several phenotypic mutants thought to lie in the gB1 structural gene between 0.345 to 0.368 map units.
Subunit vaccines extracted from chick embryo cells infected with HSV-1 or HSV-2 are described in U.S. Pat. Nos. 4,317,811 and 4,374,127. See also, Hilfenhaus et al., Develop. Biol. Standard (1982) 52:287-304, describe the preparation of nonvirulent HSV-1 X HSV-2 recombinants and deletion mutants which are shown to be effective in immunizing mice. Weis et al., Nature (1983) 302:72-74 report that gD elicits neutralizing antibodies in rabbits. Lasky et al., Biotechnology (June 1984) 527-532, report the use of this glycoprotein D for the immunization of mice. Berman et al, Science (1985) 227:1490-1492, report the use of recombinant glycoprotein D for the immunization of guinea pigs.
"Therapeutic" use of preparations of membrane proteins from HSV-infected cells for post-infection vaccine in humans are reported by Cappel et al., J. Medical Virol. (1985) 16:137-145; Dundarov, S. et al., Dev. Biol. Standard (1982) 52:351-357; and Skinner, G.R.B. et al., ibid. (1982) 52:333-34.